Receptor Mediated T and B Cell Activation

受体介导的 T 细胞和 B 细胞激活

• 批准号: 6950559
• 负责人: RICHARD J. HODES
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6950559
• 关键词: B lymphocyte; CD28 molecule; T cell receptor; T lymphocyte; antibody formation; biological signal transduction; gene rearrangement; immunoglobulin genes; immunologic memory; laboratory mouse; leukocyte activation /transformation; lymphocyte proliferation; receptor binding; receptor expression

Costimulatory B7 molecules (B7-1 or CD80; and B7-2 or CD86) are known to bind to T cell costimulatory receptors CD28 and CTLA4. Engagement of CD28 is know to transduce signals in T cells that play a critical role in T cell activation. The meachanism of signal transduction mediating T cell activation and costimulation has been studied. TCR mediated activation of T cells to proliferation and IL2 secretion was enhanced in mice deficient in cbl-b, suggesting a negative regulatory role for cbl-b under these conditions. Cbl-b deletion in fact reversed the inability of CD28-deficient mice to generate T cell-dependent Ig class switched primary and secondary antibody responses. Surprisingly, however, cbl-b deletion did not reverse the functional defect of B7 (CD80/CD86) deficient mice, indicating an unexpected difference bewtween the requirement for CD28 and for CD28 ligand B7 molecules. Moreover, cbl-b inactivation substantially reversed the immune response defect in mice deficient in both CD28 and B7. Overall, these results suggest the unanticipated conclusion that the expression of CD28 has a strong negative regulatory effect on immune response in the absence of its B7 ligands. The mechanism underlying these effects is under study employing CD28 mutants with deletion or inactivation of intracellular or extracellular domains.. Additional studies have been initiated to study the molecular pathways of T cell activation and costimulatory signaling. The relationship between members of the cbl family and another critical adapter molecule, SLP-76, are being studied using additional strategies of genetically manipulated expresssion. Experiments have indicated that inactivation of c-cbl (but not cbl-b) completely reverses the partial lethal phenotype caused by SLP-76 deficiency. In addition, c-cbl inactivation partially reverses the defect in T cell development caused by deficiency in SLP-76 or LAT, resulting in fact in a marked hyperplasia of peripheral CD4 T cells. These findings indicate an unanticipated SLP-76 (and LAT) independent signaling pathway that is facilitated by c-cbl inactivation. The biochemical basis for these effects is under study. The function of B7 in T-dependent B cell activation is being analyzed using B cells from mice that are genetically engineered to be deficient in B7 expression or to express mutated or truncated B7 products. Studies in these mice and in radiation chimeras generated from these mice will determine whether expression of B7 and signal transduction through the B7 cytoplasmic tail are required for T-dependent antibody responses, Ig class switching, and generation of memory B cells.

众所周知，共刺激B7分子（B7-1或CD80； B7-2或CD86）与T细胞共刺激受体CD28和CTLA4结合。 CD28的参与度已知会在T细胞中传递信号，在T细胞激活中起着至关重要的作用。已经研究了介导T细胞激活和共刺激的信号转导的毛刺病。 TCR介导的T细胞对增殖的激活和CBL-B缺乏小鼠的IL2分泌增强了，这表明在这些条件下CBL-B的负调节作用负面。实际上，CBL-B删除逆转了CD28缺陷小鼠无法生成T细胞依赖性IG类切换的原代和二抗反应的无力。然而，令人惊讶的是，CBL-B缺失并未逆转B7（CD80/CD86）缺陷小鼠的功能缺陷，这表明CD28和CD28配体B7分子的需求之间存在意外差异。此外，CBL-B灭活实质上逆转了缺乏CD28和B7的小鼠的免疫反应缺陷。总体而言，这些结果表明，在没有B7配体的情况下，CD28的表达对免疫反应具有强大的负调控作用。这些作用的基础机制正在采用使用CD28突变体缺失或灭活细胞内或细胞外域的研究。 已经开始了其他研究来研究T细胞激活和共刺激信号传导的分子途径。 CBL家族成员与另一个关键的适配器分子SLP-76之间的关系正在使用遗传操纵的表达的其他策略进行研究。实验表明，C-CBL（但不是CBL-B）的灭活完全逆转了由SLP-76缺乏引起的部分致命表型。此外，C-CBL失活部分逆转了由SLP-76或LAT缺乏引起的T细胞发育缺陷，实际上导致外周周围CD4 T细胞的明显增生。这些发现表明意外的SLP-76（和LAT）独立的信号通路，该通路通过C-CBL灭活促进。这些作用的生化基础正在研究。 B7在T依赖性B细胞激活中的功能正在使用来自基因工程的小鼠的B细胞进行分析，这些B细胞是基因工程的，以缺乏B7表达或表达突变或截短的B7产物。这些小鼠产生的这些小鼠和辐射嵌合体中的研究将确定B7的表达和通过B7细胞质尾部的信号转导的表达是否需要T依赖性抗体反应，IG类切换和记忆B细胞的产生。